Bone marrow T-cell infiltrates in viral infections and autoimmune diseases Alexander Tzankov

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1 Bone marrow T-cell infiltrates in viral infections and autoimmune diseases Alexander Tzankov Institute of Pathology, University Hospital Basel

2 Bone marrow T-cell infiltrates Physiological roles of mature bone marrow T-cells Bone marrow T-cells in viral infections Bone marrow T-cells in (auto)immune conditions Bone marrow T-cells and drug reactions Paraneoplastic bone marrow T-cell expansions Summary

3 Bone marrow T-cell infiltrates Physiological roles of mature bone marrow T-cells Bone marrow T-cells in viral infections Bone marrow T-cells in (auto)immune conditions Bone marrow T-cells and drug reactions Paraneoplastic bone marrow T-cell expansions Summary

4 Bone marrow T-cells, physiology

5 Bone marrow T-cells, physiology 7-9% B-cells 20-25% T-cells 8-9% CD4+ T-cells 14-18% CD8+ T-cells CD4/CD8 = % NK-cells Higher & less CD8-skewed in aspirates Clark et al. Blood 1986;67:1660

6 Bone marrow T-cells, physiology >50% of bone marrow T-cells express CD69, early activation marker HLA-DR, late activation marker Only 25% CD45RA+/RO- naïve T-cells Major source of CD8+ long-lived memory T-cells Region-specific regulative/protective function? Dean et al. Immunol Let 2005;99:94 Di Rosa. Immunol Cell Biol 2009;87:20

7 Bone marrow T-cells, physiology Bone marrow T-cells stimulated in situ by dendritic cells Cytotoxic defense against systemic blood-borne antigens Herndler-Brandstetter et al. J Leuk Biol 2012;91:197 Herndler-Brandstetter et al. J Immunol 2011;186;6965 Feuerer et al. Nat Med 2003;9:1151

8 Bone marrow T-cells, physiology Thymectomized mice become anemic T-cell infusion aid hematopoietic reconstitution Attributable to CD4+ bone marrow T-cells Dependent on MHC matching Major source of GM-CSF, IL3-6 & 13 Granulopoiesis Th17/Treg dependent Lord et al. Blood 1973; 42:395 Trainin et al. Nature 1969;221:1154 Ilstad et al. J Immunol 1984;136:28 Monteiro et al. Blood 2005; 15:105 Lee et al. J Immunol 2009;10:6377 Schwarzenberger et al. J Immunol 2000;164:4783

9 Bone marrow T-cells, physiology Monteiro et al. Blood 2005; 15:105

10 Bone marrow T-cells, physiology Di Rosa. Immunol Cell Biol 2009;87:20

11 T-cells in pathological conditions Di Rosa. Immunol Cell Biol 2009;87:20

12 Bone marrow T-cell infiltrates Physiological roles of mature bone marrow T-cells Bone marrow T-cells in viral infections Bone marrow T-cells in (auto)immune conditions Bone marrow T-cells and drug reactions Paraneoplastic bone marrow T-cell expansions Summary

13 Epstein-Barr virus Atypical peripheral T-cell lymphocytosis (CD8 skewed) Bone marrow T-cell lymphocytosis (CD8 skewed) Occasional antigenic loss for CD5 or CD7 Occasionally T-cell clonality Plasmacytosis (more prominent in immunocompromized) PTLD Hemophagocytosis/Hemophagocytic syndrome

14 Lin et al. J Clin Pathol 2007;60:101 Daikeler et a. Ann Rheum Dis 2011;70:1338 Epstein-Barr virus CD8

15 Early PTLD CD8 CD138 EBER

16 NK/TCL CD3 EBER

17 Cytomegalovirus (T-LGL) atypical peripheral lymphocytosis Occasionally T-cell clonality Bone marrow T-cell lymphocytosis (CD8 skewed) Fibrin ring granulomas Hypoplasia in immunocompromized

18 Cytomegalovirus CD3 CD3 CD8

19 Human herpes virus 8 Lympho-follicular hyperplasia Occasionally with Castleman features Plasmacytosis T-cell increase Bacon et al. Br J Haematol 2005; 127:585

20 Human herpes virus 8 LANA-1

21 Human herpes virus 8 CD3 LANA-1

22 Bone marrow T-cell infiltrates Physiological roles of mature bone marrow T-cells Bone marrow T-cells in viral infections Bone marrow T-cells in (auto)immune conditions Bone marrow T-cells and drug reactions Paraneoplastic bone marrow T-cell expansions Summary

23 Marrow T-cells and autoimmunity T-cell (T-LGL skewed) lymphocytosis Erythro- and megakaryopoietic changes Hemolysis (AIHA) & peripheral platelet consumption Anemia of chronic disease Plasmacytosis (Autoimmune) myelofibrosis Pure red cell aplasia Aplastic anemia Rizzi et al. Leuk & Lymphoma 2004;45:561 Bass et al. AJCP 2001;116:211 Voulgarelis et al. Am J Hematol 2006;81:590 Prochorec-Sobieszek et al. Arthritis Res Ther 2008;10:R55

24 Felty syndrome CD57 GrB CD8 CD3 Arthritis Res Ther 2008;10:R55

25 Marrow T-cells and autoimmunity CD57 k/l AJCP 2001;116:211 Leuk & Lymphoma 2004;45:561

26 Aplastic anemia as a collateral damage of immunosurveillance? Maciejewski et al. Folia Histochem Cytobiol 2007;45:5

27 Bone marrow T-cell infiltrates Physiological roles of mature bone marrow T-cells Bone marrow T-cells in viral infections Bone marrow T-cells in (auto)immune conditions Bone marrow T-cells and drug reactions Paraneoplastic bone marrow T-cell expansions Summary

28 Marrow T-cells and drug reactions Drugs commonly associated with T-cell increase Allopurinol Phenytoin Rituximab (Alemtuzumab) Imatinib HBV immunization Histopathology T-cell infiltration Occasionally clonal CD4 skewed, occasionally PD-1 increase Eosinophilia Myelopoietic maturation arrest Granulomas Villard et al. Br J Haematol 2000;110:230 Braziel et al. Blood 2002;100:435 Raynaud et al. Hum Pathol 2008;39:194 Johns et al. MJHID 2010;6207

29 Marrow T-cells and drug reactions Criado et al. An Bras Dermatol 2012;87:435

30 Allopurinol induced DRESS PAS CD3 PD-1

31 T-cell expansion after Phenytoin PAS CD3 CD4 CD8

32 T-cell aggregates after Rituximab CD3

33 Bone marrow T-cell infiltrates Physiological roles of mature bone marrow T-cells Bone marrow T-cells in viral infections Bone marrow T-cells in (auto)immune conditions Bone marrow T-cells and drug reactions Paraneoplastic bone marrow T-cell expansions Summary

34 Paraneoplastic T-cell expansions B-cell lymphomas Marginal zone B-cell lymphoma Lymphoplasmacytic lymphoma Follicular lymphoma AML, particularly MLL rearranged MDS MPN Thymomas Systemic mastocytosis Horny et al. J Clin Pathol 2003;56:575 Magalhães et al. Leuk Res 2002;26:525 Smith et al. AJCP 1994;102:447 Cervantes et al. Br J Haematol 1988;70:279

35 Accompanying T-cells in MZL CD5 CD20

36 Accompanying T-cells in AML M5A CD11c CD3

37 Bone marrow T-cell infiltrates Physiological roles of mature bone marrow T-cells Bone marrow T-cells in viral infections Bone marrow T-cells in (auto)immune conditions Bone marrow T-cells and drug reactions Paraneoplastic bone marrow T-cell expansions Summary

38 Summary Important physiological role of T-cells in the bone marrow Rise and CD8 skewing in viral and autoimmune diseases Look for viropathic effects and ask for clinics, serology & PCR Rise and CD4 skewing in adverse drug reactions Ask for Attack, mask or accompany neoplastic diseases Look for